High-risk features of early relapse in newly-diagnosed multiple myeloma: The impact of cytogenetics and response to initial therapy

Patients with newly-diagnosed multiple myeloma (MM) who experience early relapse (ER) have dismal overall survival (OS). Their prospective identification, either before or soon after treatment initiation, is paramount to use alternative approaches and prevent ER. In this study, we investigated the frequency and disease characteristics of ER during the first 18 months after treatment initiation (ER18), in a series of 1215 newly-diagnosed MM patients enrolled in four PETHEMA/GEM clinical trials for the transplant-eligible and transplant-ineligible populations. ER18 was observed in 266 of the 1215 patients (22%) and resulted in a median OS of 19 versus 114 months in cases without ER18. When compared to the ISS and the presence of ≥2 high-risk cytogenetic abnormalities, a modified version of the new high-risk definition from the International Myeloma Society (mHR-IMS) showed the most balanced negative and positive predictive values of ER18 (83.5% and 40%, respectively). In addition to the mHR-IMS, an ECOG = 2, ISS 3, and calcium levels ≥ 11 mg/dL were independently associated with ER18. These variables were modeled into a predictive score in which the rates of ER18 were 2%, 24.5%, and 59% in patients with low-, intermediate-, and high-risk score. The risk of ER18 and OS were modulated by the VGPR status at 6–9 months after treatment initiation. In conclusion, we present a risk model that predicts ER18 and can be readily applied in clinical trials and routine practice to identify treatment strategies empowered to prevent ER18 and improve survival outcomes of newly-diagnosed patients with functional high-risk MM.